Genomic Analysis of Leukocyte mRNA Suggests Immune Predisposition to Hemorrhagic Transformation in Ischemic Stroke (S42.006)

OBJECTIVE: Determine whether ischemic strokes that develop hemorrhagic transformation have differences in leukocyte RNA expression prior to treatment with thrombolytic therapy. BACKGROUND: Hemorrhagic transformation (HT) is a major complication of ischemic stroke that worsens outcomes and increases mortality. Disruption of the blood brain barrier is a central feature to HT pathogenesis, and leukocytes may contribute to this process. We sought to. DESIGN/METHODS: Stroke patient blood samples were obtained prior to treatment with thrombolysis, and leukocyte RNA assessed by microarray analysis. Strokes that developed HT (n=11) were compared to strokes without HT (n=33) and controls (n=14). Genes were identified (corrected p-value |1.2|) and functional analysis performed. RNA prediction of HT in stroke was evaluated using cross-validation, and in a second stroke cohort (n=23). RESULTS: Ischemic strokes that developed HT had differential expression of 29 genes in circulating leukocytes prior to treatment with thrombolytic. A panel of 6 genes could predict strokes that later developed HT with 86.4% accuracy. Key pathways involved in HT of human stroke are described, including amphiregulin, a growth factor that regulates matrix metalloproteinase-9; a shift in transforming growth factor-beta signaling involving SMAD4, INPP5D and IRAK3; and a disruption of coagulation factors V and VIII. CONCLUSIONS: Identified genes correspond to differences in inflammation and coagulation that may predispose to HT in ischemic stroke. Given the adverse impact of HT on stroke outcomes, further evaluation of identified genes and pathways is warranted to determine their potential as therapeutic targets to reduce HT and as markers of HT risk. Supported by: NINDS (NS056302, NS075035), the American Heart Association. Disclosure: Dr. Jickling has nothing to disclose. Dr. Stamova has nothing to disclose. Dr. Zhan has nothing to disclose. Dr. Ander has nothing to disclose. Dr. Liu has nothing to disclose. Dr. Rothstein has nothing to disclose. Dr. Verro has received personal compensation for activities with Boehringer Ingelheim Pharmaceuticals, Inc. Dr. Khoury has nothing to disclose. Dr. Jauch has nothing to disclose. Dr. Pancioli has nothing to disclose. Dr. Broderick has received personal compensation for activities as a speaker. Dr. Broderick has received research support from EKOS Corporation, Concentric Inc., and Genentech, Inc. Dr. Sharp has nothing to disclose.